SUMMARY There has been a significant interest in the effects of the gut microbiome on brain function. Reports have linked gut microbes with an array of brain disorders ranging from anorexia to autism. The gut microbe-neuron interface is therefore emerging as an attractive target to treat neurological disorders from the gut surface. Unfortunately, mechanistic explanations of how nerves sense microbes are scant. Here, I propose that enteroendocrine cells serve as sensory transducers of bacterial signals to nerves. Enteroendocrine cells are electrically excitable cells that, unlike nerves, are directly exposed to luminal ligands. Although enteroendocrine cells are commonly recognized for their role in hormone secretion, hence their name, my research team recently discovered that enteroendocrine cells form synaptic-like contacts with neurons. Some of these belong to the vagus nerve. This neural circuit between enteroendocrine cells and vagal neurons is a direct path for sensory transduction from gut to brain. A path through which bacteria signals can modulate brain function. Enteroendocrine cells of the mouse colon express bacterial toll-like receptors. These receptors are membrane proteins that recognize pathogen-associated molecular patterns. Our preliminary data show that these cells express specific members of the toll-like receptor family. Moreover, defined ligands to these receptors trigger current responses in enteroendocrine cells. With the support of a R03 Small Grant Program for NIDDK K01 awardees, our objective is to define if toll-like receptors mediate the transduction of bacterial stimuli from enteroendocrine cells to neurons. We will test the hypothesis in two specific aims: 1) to define if enteroendocrine cells are electrically excitated by toll- like receptor ligands; and 2) to determine if bacterial stimuli are transduced from enteroendocrine cells onto neurons. My laboratory has expertise in electrophysiology and transgenic animals in which enteroendocrine cells of the colon express fluorescence proteins and calcium reporters. Combined with our electrophysiology capabilities, these animal models allow us to interrogate the electrical activity of individual enteroendocrine cells both in vitro and in vivo. This project will be a foundation to unveil a neural path through which the brain senses gut bacteria.